Dietary fat can profoundly influence lipoprotein levels and coronary heart disease risk. However, there is great variation among people in diet responsiveness, which presumably affects their susceptibility to atherosclerotic disease. We intend to use our expertise in lipoprotein transport protein gene molecular biology and transgenic animals, as well as our ability to perform inpatient metabolic studies to investigate gene-diet interactions that influence lipoprotein metabolism. The following specific aims are proposed: A. Characterize how dietary fat and cholesterol influence HDL metabolism. In humans a high fat-high cholesterol diet increases HDL-C levels by increasing HDL apolipoprotein TR. We have modeled this diet-induced increase in HDL-C levels in control and HuAITg mice and intend to determine the mechanism involved. In addition, we will test in HuCETPTg mice the hypothesis that CETP is a major modulator of the effect of the high fat-high cholesterol diet on HDL-C levels. B. Determine the role of apo E in diet responsiveness and HDL metabolism. We propose to create apo E deficient mice and transgenic mice expressing specific human apo E alleles to test the role of apo E in diet responsiveness, cholesterol absorption, reverse cholesterol transport and HDL metabolism. C. Identify the physiological function(s) of apo A-IV. We aim to create apo A-IV deficient mice and transgenic mice expressing human apo A-IV to test the role of apo A-IV in dietary fat and fat soluble vitamin absorption, diet responsiveness, reverse cholesterol transport, and HDL metabolism. D. Study the role of the lipoprotein processing proteins in HDL metabolism. In humans HDL-C levels correlate inversely with apo A- I FCR, which in turn correlate inversely with HDL size. To prove a cause and effect relationship between HDL size, apo A-I FCR, and HDL-C levels, we will study mice transgenic for CETP or LPL or HL. If expression of these transgenes results in a change in HDL size, we will examine the effect this might have on HDL CE and apo A-I metabolism as well as HDL-C levels. These studies could suggest mechanisms and candidate genes that might be particularly important in regulating HDL-C levels in humans. E. Genetic control of lipoprotein levels and diet responsiveness studied in MZ and DZ twins. Twin studies have been used to estimate the extent of genetic control of many different phenotypes in humans. The difference in within pair similarity between MZ and DZ twins indicates how much of the phenotype is genetically controlled. We aim to study lipoprotein levels and related parameters in MZ and DZ twin pairs on low and high fat diets under metabolic ward conditions to estimate the genetic control of lipoprotein levels on a fixed diet and the genetic control of diet responsiveness.